Enteropathogenic Escherichia coli (EPEC) is a leading cause of infant diarrhea and was the first E. coli shown to cause gastroenteritis. EPEC continues to be a significant cause of infantile diarrhea in developing nations contributing to high morbidity and mortality. EPEC forms small microcolonies on the surface of infected epithelial cells followed by intimate contact and localized degeneration of the epithelial brush border microvilli, cumulating in an attaching and effacing (A/E) lesion. The A/E lesion (or pedestal) is associated with the assembly of highly organized cytoskeletal structures in epithelial cells immediately beneath the adherent bacteria that include the cytoskeletal components actin, α-actinin, myosin light chain, ezrin, and talin.
EPEC is a member of a group of pathogenic organisms, collectively known as attaching and effacing pathogens, that adhere to host cells and cause localized accumulation of host actin beneath adherent organisms. Pathogens in this group include enterohemorrhagic E. coli (EHEC, the causative agent of hemorrhagic colitis and hemolytic uremic syndrome) and several other human and animal pathogens, including Citrobacter rodentium and Hafnia alvei. 
A three-stage model describes enteropathogenic E. coli pathogenesis. An initial localized adherence to epithelial cells, mediated by a type IV fimbria, is followed by the activation of host epithelial cell signal transduction pathways and intimate attachment to host epithelial cells. These final two steps are collectively known as attaching and effacing. The signal transduction in the host epithelial cells involves activation of host cell tyrosine kinase activity leading to tyrosine phosphorylation of a 90 kilodalton (kDa) host membrane protein, Hp90, and fluxes of intracellular inositol phosphate (IP3) and calcium. Following this signal transduction, the bacteria adheres intimately to the surface of the epithelial cell, accompanied by damage to host epithelial cell microvilli and accumulation of cytoskeletal proteins beneath the bacteria.
Recently, some of the bacterial components involved in pedestal formation have been identified. EPEC possess a virulence plasmid which encodes the bundle forming pilus and a positive virulence factor regulator, Per. All of the genes which encode products that are necessary for pedestal formation are found within a 35 kilobase par (kb) pathogenicity island in the E. coli chromosome. Within the Locus of Enterocyte Effacement (LEE) region are several genes whose products have different functions, including a type III secretion apparatus proteins, secreted effector molecules and their chaperones, and intimin.
Type III secretion systems are being increasingly found in many pathogenic Gram-negative organisms, and the role of the EPEC type III secretion system is to secrete proteins necessary for formation of the A/E lesion. At least two proteins secreted by the EPEC secretion system, EspA and EspB, are necessary for activating EPEC induced signals in epithelial cells. These signals include calcium and inositol phosphate fluxes, and tyrosine phosphorylation of Hp90. Mutations in espA or espB, or those in the type III secretion system (sep and cfm), are unable to signal or induce binding of the EPEC adhesin intimin to epithelial cell surfaces.
Intimin is the product of a bacterial chromosomal LEE locus, eaeA, and is a 94 kDa EPEC outer membrane protein needed for intimate adherence. Mutants defective in eaeA form immature A/E lesions and do not organize phosphotyrosine proteins and cytoskeletal components beneath adherent bacteria, although epithelial signal transduction is still activated. Intimin participates in reorganization of the underlying host cytoskeleton after other bacterial factors (EspA and EspB) stimulate epithelial signal transduction.
Intimin binding to host cells also stimulates a second wave of signal transduction inside the mammalian cell, including tyrosine phosphorylation of phospholipase Cγ. In cultured cells intimin binds to the tyrosine phosphorylated form of Hp90, but only if mammalian cells have been preinfected with EPEC strains possessing an intact type II secretion system capable of secreting EspA and EspB. However, little was known about the identity of Hp90 other than it is tyrosine phosphorylated following EPEC infection and that it serves as a receptor for intimin. Phosphotyrosine proteins (presumably Hp90) are concentrated at the tip of the pedestal immediately beneath EPEC, but phosphotyrosine residues are not surface exposed in unpermeabilized cells. Biochemically, Hp90 behaves as an integral host membrane protein, and appears to be highly conserved. It also appears to play a key role in organizing polymerized actin under the adherent bacteria once it binds intimin.